What are the treatment options for restless legs syndrome?

Treatment Options for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for patients with restless legs syndrome due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1, 2

Initial Assessment and Management

• Check serum iron studies, including ferritin and transferrin saturation, in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1, 2
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
• Address potential exacerbating factors, including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1, 2

Treatment Algorithm

First-Line Treatments

1. Iron Therapy (when indicated):

   • Oral ferrous sulfate for patients with ferritin ≤75 ng/mL or transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 2
   • IV ferric carboxymaltose for patients with appropriate iron parameters who don't respond to oral therapy (strong recommendation, moderate certainty) 1, 2

2. Alpha-2-delta Ligands:

   • Gabapentin (strong recommendation, moderate certainty) 1, 2
   • Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 2
   • Pregabalin (strong recommendation, moderate certainty) 1, 2

Second-Line and Alternative Treatments

• Extended-release opioids are conditionally recommended, particularly for refractory cases or when treating augmentation from dopaminergic agents 1
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1
• Dipyridamole is conditionally recommended (low certainty of evidence) 1

Medications to Avoid or Use with Caution

• The American Academy of Sleep Medicine suggests against the standard use of dopaminergic agents due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2

• Specifically not recommended:

  • Levodopa (conditional recommendation against, very low certainty) 1, 2
  • Pramipexole (conditional recommendation against, moderate certainty) 1, 2
  • Ropinirole (conditional recommendation against, moderate certainty) 1, 3
  • Transdermal rotigotine (conditional recommendation against, low certainty) 1
  • Cabergoline (strong recommendation against, moderate certainty) 1, 2

• Also not recommended: bupropion, carbamazepine, clonazepam, valproic acid, and valerian 1

Special Populations

End-Stage Renal Disease

• Gabapentin (conditional recommendation, very low certainty) 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1
• Vitamin C (conditional recommendation, low certainty) 1

Pediatric RLS

• Ferrous sulfate for iron deficiency (conditional recommendation, very low certainty) 1

Pregnancy

• Treatment selection should consider pregnancy-specific safety profiles 2
• Non-pharmacologic approaches may be preferred 2

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on medication 1, 4
• Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1, 4
• Management options include:
  • Taking medication doses earlier in the day 1
  • Splitting existing doses into early evening and bedtime doses 1
  • Considering opioids for treating augmentation 1, 4
  • Substituting an alpha-2-delta ligand for the dopaminergic agent 4

Clinical Pearls

• When switching from dopaminergic agents due to augmentation, add the new medication (alpha-2-delta ligand or opioid) first before attempting to taper the dopaminergic agent to avoid rebound symptoms 4
• Once adequate doses or symptom relief are achieved with the second agent, very slow down-titration and discontinuation of the dopaminergic agent is recommended 4
• Most patients with RLS also have periodic limb movements during sleep, although this is not part of the clinical diagnostic criteria 5, 6
• Good sleep hygiene and avoidance of alcohol, caffeine, and nicotine may improve symptoms 7